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Agreed incomplete CORE SAFETY PROFILE OF Tibolone The CPS is incomplete with regard to sections 4.4 (renal impairment) and 4.5 (interactions). MAH intend to implement the final text after the PSUR assessment procedure together with the final Core SPC texts after completion of the PhVWP discussions in a type II variation that will be submitted in all EU countries, as soon as both procedures are completed. Before applying for the type 1b variation, the generic MAHs should await an agreed complete CSP that will be circulated about four month from today. 2 SE/H/PSUR/0006/002 4.3 Contraindications 4.4 Tibolone PSUR WS incomplete Agreed Core Safety Profile Pregnancy and lactation Known, past or suspected breast cancer - tibolone increased the risk of breast cancer recurrence in a placebo-controlled trial Known or suspected estrogen-dependent malignant tumors (e.g. endometrial cancer) Undiagnosed genital bleeding Untreated endometrial hyperplasia Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism) Any history of arterial thromboembolic disease (e.g. angina, myocardial infarction, stroke or TIA) Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal Known hypersensitivity to the active substance or to any of the excipients Porphyria Special warnings and precautions for use For the treatment of postmenopausal symptoms, tibolone should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and tibolone should only be continued as long as the benefit outweighs the risk. The risks of stroke, breast cancer and, in women with an intact uterus, endometrial cancer (see below and section 4.8) for each woman should be carefully assessed, in the light of her individual risk factors and bearing in mind the frequency and characteristics of both cancers and stroke, in terms of their response to treatment, morbidity and mortality. Medical examination/follow-up Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see ‘Breast cancer’ below). Investigations, including mammography, should be carried out in accordance with currently 3 SE/H/PSUR/0006/002 Tibolone PSUR WS incomplete Agreed Core Safety Profile accepted screening practices, modified to the clinical needs of the individual. Conditions which need supervision If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Livial, in particular: - Leiomyoma (uterine fibroids) or endometriosis - A history of, or risk factors for, thromboembolic disorders (see below) - Risk factors for estrogen dependent tumors, e.g. 1st degree heredity for breast cancer - Hypertension - Liver disorders (e.g. liver adenoma) - Diabetes mellitus with or without vascular involvement - Cholelithiasis - Migraine or (severe) headache - Systemic lupus erythematosis - A history of endometrial hyperplasia (see below) - Epilepsy - Asthma - Otosclerosis Reasons for immediate withdrawal of therapy: Therapy should be discontinued in case a contraindication is discovered and in the following situations: Jaundice or deterioration in liver function Significant increase in blood pressure New onset of migraine-type headache Endometrial cancer The available data from randomized controlled trials are conflicting, however, observational studies have consistently shown that women who are prescribed tibolone in normal clinical practice are at an increased risk of having endometrial cancer diagnosed (see Section 4.8). In these studies risk increased with increasing duration of use. Tibolone increases endometrial wall thickness, as measured by transvaginal ultrasound. Break-through bleeding and spotting may occur during the first months of treatment (see section 5.1). Women should be advised to report any break-through bleeding or spotting if it is still present after 6 months of 4 SE/H/PSUR/0006/002 Tibolone PSUR WS incomplete Agreed Core Safety Profile treatment, if it starts beyond that time or if it continues after treatment has been discontinued. The woman should be referred for gynecological investigation, which is likely to include endometrial biopsy to exclude endometrial malignancy. Breast cancer Evidence with respect to breast cancer risk in association with tibolone is inconclusive. The Million Women Study (MWS) has identified a significant increase in the risk of breast cancer in association with use of the 2.5mg dose. This risk became apparent within a few years of use and increased with duration of intake, returning to baseline within a few (at most five) years after stopping treatment, see section 4.8. These results could not be confirmed in a study using the General Practitioners Research Database. Venous thromboembolism Estrogen or estrogen-progestogen HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomized controlled trial and epidemiological studies found a two- to threefold higher risk for users compared with non-users. For non-users it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later. It is unknown whether Livial carries the same level of risk. Generally recognized risk factors for VTE include a personal history or family history, severe obesity (BMI > 30 kg/m2) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE. Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT. 5 SE/H/PSUR/0006/002 Tibolone PSUR WS incomplete Agreed Core Safety Profile The risk of VTE may be temporarily increased with prolonged immobilization, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilization is liable to follow elective surgery, particularly abdominal surgery or orthopedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilized. If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnea). Coronary artery disease (CAD) There is no evidence from randomized controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomized controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products. Stroke Tibolone increases the risk of ischaemic stroke from the first year of treatment (see section 4.8). The baseline risk of stroke is strongly agedependent and so the effect of tibolone is greater with older age. Ovarian cancer Long-term (at least 5-10 years) use of estrogen-only HRT products in hysterectomized women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than estrogen-only products. Other conditions Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 6 SE/H/PSUR/0006/002 4.5 Tibolone PSUR WS incomplete Agreed Core Safety Profile Livial is not intended for contraceptive use. Treatment with Livial results in a marked dose-dependent decrease in HDL cholesterol (from -16.7% with a 1.25 mg dose to -21.8% for the 2.5 mg dose after 2 years). Total triglycerides and lipoprotein(a) levels were also reduced. The decrease in total cholesterol and VLDL-C levels was not dose-dependent. Levels of LDL-C were unchanged. The clinical implication of these findings is not yet known. Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or HRT, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition. Treatment with Livial results in a very minor decrease of thyroid binding globulin (TBG) and total T4. Levels of total T3 are unaltered. Livial decreases the level of sex-hormone-binding globulin (SHBG), whereas the levels of corticoid binding globulin (CBG) and circulating cortisol are unaffected. There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined conjugated estrogens and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products. Interaction with other medicinal products and other forms of interaction Since Livial may increase blood fibrinolytic activity, it may enhance the effect of anticoagulants. This effect has been demonstrated with warfarin. Caution should therefore be exercised during the simultaneous use of Livial and anticoagulants, especially when starting or stopping concurrent Livial treatment. If necessary, the dose of warfarin should be adjusted. There is limited information regarding pharmacokinetic interactions with tibolone. An in vivo study showed that simultaneous treatment of tibolone affects pharmacokinetics of the cytochrome P450 3A4 substrate midazolam to a moderate extent. Based on this, drug interactions with other CYP3A4 substrates might be expected. CYP3A4 inducing compounds such as barbiturates, carbamazepine, hydantoins and rifampicin may enhance the metabolism of tibolone and thus 7 SE/H/PSUR/0006/002 Tibolone PSUR WS incomplete Agreed Core Safety Profile affect its therapeutic effect. Herbal preparations containing St.John`s wort (Hypericum Perforatum) may induce the metabolism of oestrogens and progestagens via CYP3A4. Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile. 4.6 Pregnancy and lactation Livial is contraindicated during pregnancy (see section 4.3). If pregnancy occurs during medication with Livial, treatment should be withdrawn immediately. For Livial no clinical data on exposed pregnancies are available. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Livial is contraindicated during lactation (see section 4.3). 4.7 Effects on ability to drive and use machines Livial is not known to have any effects on alertness and concentration. 4.8 Undesirable effects This section describes undesirable effects, which were registered in 21 placebo-controlled studies (including the LIFT study), with 4079 women receiving therapeutic doses (1.25 or 2.5 mg) of tibolone and 3476 women receiving placebo. The duration of treatment in these studies ranged from 2 months to 4.5 years. Table 1 shows the undesirable effects that occurred statistically significantly more frequently during treatment with tibolone than with placebo. Table 1 Undesirable effects of Livial System organ class Common >1%,<10% Metabolism and nutrition disorders Gastrointestinal disorders Uncommon >0.1%,<1% Rare >0.01%,<0.1% Oedema** Lower abdominal pain Abdominal discomfort** Abnormal hair growth Acne Hepatobiliary disorders Skin and subcutaneous tissue disorders Reproductive system and breast Vaginal discharge disorders Endometrial wall thickening Breast discomfort Fungal infection Vaginal mycosis Pruritis** 8 SE/H/PSUR/0006/002 Postmenopausal haemorrhage Breast tenderness Genital pruritus Vaginal candidiasis Vaginal haemorrhage Pelvic pain Cervical dysplasia Genital discharge Vulvovaginitis Tibolone PSUR WS incomplete Agreed Core Safety Profile Nipple pain Investigations Weight increase Abnormal cervical smear* * The majority consisted of benign changes. Cervix pathology (cervical carcinoma) was not increased with tibolone compared to placebo. ** These adverse reactions were identified through post-marketing surveillance. The frequency category was estimated based on relevant clinical trials. In market use, other undesirable effects that have been observed include: dizziness, rash, seborrheic dermatosis, headache, migraine, visual disturbances (including blurred vision), depression, effects on the musculoskeletal system such as arthralgia or myalgia and changes in liver function parameters. Breast cancer The MWS reported that, compared with never users, the use of various types of estrogen-progestogen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88-2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21-1.40) or use of 2.5 mg tibolone (RR=1.45; 95%CI 1.251.68). The MWS has estimated, from the known average incidence of breast cancer in developed countries, that: For women not using HRT or tibolone, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years. For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be - For users of estrogen-only replacement therapy, between 0 and 3 (best estimate = 1.5) for 5 years’ use between 3 and 7 (best estimate = 5) for 10 years’ use. - For users of estrogen-progestogen combined HRT, between 5 and 7 (best estimate = 6) for 5 years’ use between 18 and 20 (best estimate = 19) for 10 years’ use 9 SE/H/PSUR/0006/002 Tibolone PSUR WS incomplete Agreed Core Safety Profile For women who use tibolone the number of additional cases of breast cancer was comparable with that for estrogen-only use. Endometrial cancer The randomized placebo controlled trial that included women who had not been screened for endometrial abnormalities at baseline, and therefore reflected clinical practice, identified the highest risk of endometrial cancer, (LIFT study, mean age 68 years). In this study, no cases of endometrial cancer were diagnosed in the placebo group (n=1,773) after 2.9 years compared with 4 cases of endometrial cancer in the tibolone group (n=1,746). This corresponds to a diagnosis of 0.8 additional case of endometrial cancer in every 1000 women who used tibolone for one year in this study (see section 4.4)." Stroke A 2.9 year randomized controlled study has estimated a 2.2-fold increase in the risk of stroke in women (mean age 68 years) who used 1.25 mg tibolone (28/2249) compared with placebo (13/2257). The majority (80%) of strokes were ischaemic. The baseline risk of stroke is strongly age-dependent. Thus, the baseline incidence over a 5 year period is estimated to be 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. For women who use tibolone for 5 years, the number of additional cases would be expected to be about 4 per 1000 users aged 50-59 years and 13 per 1000 users aged 60-69 years. Other adverse reactions have been reported in association with estrogenprogestogen treatment: - Estrogen-dependent neoplasms benign and malignant, e.g., endometrial carcinoma - Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among HRT users than among non-users. For further information, see sections 4.3 and 4.4 - Myocardial infarction - Gall bladder disease - Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura - Probable dementia (see section 4.4) 10 SE/H/PSUR/0006/002 4.9 Tibolone PSUR WS incomplete Agreed Core Safety Profile Overdose The acute toxicity of tibolone in animals is very low. Therefore, toxic symptoms are not expected to occur, even when several tablets are taken simultaneously. In cases of acute overdose, nausea, vomiting and vaginal bleeding in females may occur. No specific antidote is known. Symptomatic treatment can be given if necessary.